CAIX-Mediated Control of LIN28/let-7Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia

0534747 - ÚMG 2021 RIV CH eng J - Journal Article
Gibadulinová, A. - Bullova, P. - Strnad, Hynek - Pohlodek, K. - Jurkovičová, D. - Takacova, M. - Pastorekova, S. - Svastova, E.
CAIX-Mediated Control of LIN28/let-7Axis Contributes to Metabolic Adaptation of Breast Cancer Cells to Hypoxia.
International Journal of Molecular Sciences. Roč. 21, č. 12 (2020), č. článku 4299. E-ISSN 1422-0067
Institutional support: RVO:68378050
Keywords : carbonic anhydrase IX * hypoxia * lin28 * let-7axis * metabolism
OECD category: Biochemistry and molecular biology
Impact factor: 5.924, year: 2020
Method of publishing: Open access
https://www.mdpi.com/1422-0067/21/12/4299

Solid tumors, including breast cancer, are characterized by the hypoxic microenvironment, extracellular acidosis, and chemoresistance. Hypoxia marker, carbonic anhydrase IX (CAIX), is a pH regulator providing a selective survival advantage to cancer cells through intracellular neutralization while facilitating tumor invasion by extracellular acidification. The expression of CAIX in breast cancer patients is associated with poor prognosis and metastases. Importantly, CAIX-positive hypoxic tumor regions are enriched in cancer stem cells (CSCs). Here we investigated the biological effects ofCA9-silencing in breast cancer cell lines. We found that CAIX-downregulation in hypoxia led to increased levels oflet-7(lethal-7) family members. Simultaneously with the increase oflet-7miRNAs in CAIX-suppressed cells, LIN28 protein levels decreased, along with downstream metabolic pathways: pyruvate dehydrogenase kinase 1 (PDK1) and phosphorylation of its substrate, pyruvate dehydrogenase (PDH) at Ser-232, causing attenuation of glycolysis. In addition to perturbed glycolysis, CAIX-knockouts, in correlation with decreased LIN28 (as CSC reprogramming factor), also exhibit reduction of the further CSC-associated markers NANOG (Homeobox protein NANOG) and ALDH1 (Aldehyde dehydrogenase isoform 1). Oppositely, overexpression of CAIX leads to the enhancement of LIN28, ALDH1, and NANOG. In conclusion, CAIX-driven regulation of the LIN28/let-7axis augments glycolytic metabolism and enhances stem cell markers expression during CAIX-mediated adaptation to hypoxia and acidosis in carcinogenesis.
Permanent Link: http://hdl.handle.net/11104/0312927